Biosynthesis of novel desferrioxamine derivatives requires unprecedented crosstalk between separate NRPS-independent siderophore pathways.

Iron is essential to many biological processes but its poor solubility in aerobic environments restricts its bioavailability. To overcome this limitation, bacteria have evolved a variety of strategies, including the production and secretion of iron-chelating siderophores. Here, we describe the discovery of four series of siderophores from Streptomyces ambofaciens ATCC23877, three of which are unprecedented. MS/MS-based molecular networking revealed that one of these series corresponds to acylated desferrioxamines (acyl-DFOs) recently identified from S. coelicolor. The remaining sets include tetra- and penta-hydroxamate acyl-DFO derivatives, all of which incorporate a previously undescribed building block. Stable isotope labeling and gene deletion experiments provide evidence that biosynthesis of the acyl-DFO congeners requires unprecedented crosstalk between two separate non-ribosomal peptide synthetase (NRPS)-independent siderophore (NIS) pathways in the producing organism. Although the biological role(s) of these new derivatives remain to be elucidated, they may confer advantages in terms of metal chelation in the competitive soil environment due to the additional bidentate hydroxamic functional groups. The metabolites may also find application in various fields including biotechnology, bioremediation, and immuno-PET imaging.IMPORTANCEIron-chelating siderophores play important roles for their bacterial producers in the environment, but they have also found application in human medicine both in iron chelation therapy to prevent iron overload and in diagnostic imaging, as well as in biotechnology, including as agents for biocontrol of pathogens and bioremediation. In this study, we report the discovery of three novel series of related siderophores, whose biosynthesis depends on the interplay between two NRPS-independent (NIS) pathways in the producing organism S. ambofaciens-the first example to our knowledge of such functional cross-talk. We further reveal that two of these series correspond to acyl-desferrioxamines which incorporate four or five hydroxamate units. Although the biological importance of these novel derivatives is unknown, the increased chelating capacity of these metabolites may find utility in diagnostic imaging (for instance, 89Zr-based immuno-PET imaging) and other applications of metal chelators.

Temporal Variation and Persistence of Methane Emissions from Shallow Water Oil and Gas Production in the Gulf of Mexico.

Methane emissions from the oil and gas supply chain can be intermittent, posing challenges for monitoring and mitigation efforts. This study examines shallow water facilities in the US Gulf of Mexico with repeat atmospheric observations to evaluate temporal variation in site-specific methane emissions. We combine new and previous observations to develop a longitudinal study, spanning from days to months to almost five years, evaluating the emissions behavior of sites over time. We also define and determine the chance of subsequent detection (CSD): the likelihood that an emitting site will be observed emitting again. The average emitting central hub in the Gulf has a 74% CSD at any time interval. Eight facilities contribute 50% of total emissions and are over 80% persistent with a 96% CSD above 100 kg/h and 46% persistent with a 42% CSD above 1000 kg/h, indicating that large emissions are persistent at certain sites. Forward-looking infrared (FLIR) footage shows many of these sites exhibiting cold venting. This suggests that for offshore, a low sampling frequency over large spatial coverage can capture typical site emissions behavior and identify targets for mitigation. We further demonstrate the preliminary use of space-based observations to monitor offshore emissions over time.

KidneyGPS: a user-friendly web application to help prioritize kidney function genes and variants based on evidence from genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. By combining these findings with post-GWAS information (e.g., statistical fine-mapping to identify independent association signals and to narrow down signals to causal variants; or different sources of annotation data), new hypotheses regarding physiology and disease aetiology can be obtained. These hypotheses need to be tested in laboratory experiments, for example, to identify new therapeutic targets. For this purpose, the evidence obtained from GWAS and post-GWAS analyses must be processed and presented in a way that they are easily accessible to kidney researchers without specific GWAS expertise. MAIN: Here we present KidneyGPS, a user-friendly web-application that combines genetic variant association for estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics consortium with annotation of (i) genetic variants with functional or regulatory effects ("SNP-to-gene" mapping), (ii) genes with kidney phenotypes in mice or human ("gene-to-phenotype"), and (iii) drugability of genes (to support re-purposing). KidneyGPS adopts a comprehensive approach summarizing evidence for all 5906 genes in the 424 GWAS loci for eGFR identified previously and the 35,885 variants in the 99% credible sets of 594 independent signals. KidneyGPS enables user-friendly access to the abundance of information by search functions for genes, variants, and regions. KidneyGPS also provides a function ("GPS tab") to generate lists of genes with specific characteristics thus enabling customizable Gene Prioritisation (GPS). These specific characteristics can be as broad as any gene in the 424 loci with a known kidney phenotype in mice or human; or they can be highly focussed on genes mapping to genetic variants or signals with particularly with high statistical support. KidneyGPS is implemented with RShiny in a modularized fashion to facilitate update of input data ( https://kidneygps.ur.de/gps/ ). CONCLUSION: With the focus on kidney function related evidence, KidneyGPS fills a gap between large general platforms for accessing GWAS and post-GWAS results and the specific needs of the kidney research community. This makes KidneyGPS an important platform for kidney researchers to help translate in silico research results into in vitro or in vivo research.

The Relationship Between Directly Observed Therapy for Chlamydia Infections and Retesting Rates in an Adolescent Population.

BACKGROUND: Chlamydia trachomatis is the most common reportable sexually transmitted infection in the United States, with >60% of reported cases occurring in individuals aged 15 to 24 years. US practice guidelines recommend directly observed therapy (DOT) for the treatment of chlamydia in adolescents, but almost no research has been done to evaluate whether DOT results in improved outcomes. METHODS: We conducted a retrospective cohort study of adolescents who sought care at 1 of 3 clinics within a large academic pediatric health system for a chlamydia infection. The study outcome was return for retesting within 6 months. Unadjusted analyses were performed using χ2 , Mann-Whitney U , and t tests, and adjusted analyses were performed using multivariable logistic regression. RESULTS: Of the 1970 individuals included in the analysis, 1660 (84.3%) received DOT and 310 (15.7%) had a prescription sent to a pharmacy. The population was primarily Black/African American (95.7%) and female (78.2%). After controlling for confounders, individuals who had a prescription sent to a pharmacy were 49% (95% confidence interval, 31%-62%) less likely than individuals who received DOT to return for retesting within 6 months. CONCLUSIONS: Despite clinical guidelines recommending the use of DOT for chlamydia treatment in adolescents, this is the first study to describe the association between DOT and an increase in the number of adolescents and young adults who return for sexually transmitted infection retesting within 6 months. Further research is needed to confirm this finding in diverse populations and explore nontraditional settings for the provision of DOT.

Data Gap: Air Quality Networks Miss Air Pollution from Concentrated Animal Feeding Operations.

In the U.S., the agricultural sector is the largest controllable source of several air pollutants, including ammonia (NH3), which is a key precursor to PM2.5 formation. Livestock waste is the dominant contributor to ammonia emissions. In contrast to most controllable air pollutants, satellite records show ammonia mixing ratios are rising. The number of confined animal feeding operations (CAFOs) that generate considerable livestock waste is also increasing. Spatial and temporal trends in USDA-reported animal numbers normalized by county area at medium and large CAFOs provide plausible explanations for patterns in satellite-derived NH3 over the contiguous U.S. (CONUS). The correlation between summertime ammonia derived from the European Space Agency's (ESA) Infrared Atmospheric Sounding Interferometer (IASI) and CAFO animal unit density in 2017 is positive and significant (r = 0.642; p ≈ 0). The temporal changes from 2002 to 2017 in animal unit density and NH3 derived from NASA's Atmospheric Infrared Sounder (AIRS) are spatially similar. Trends and ambient concentrations of PM2.5 mass in agricultural regions are difficult to assess relative to those of urban population centers given the sparseness of rural monitors in regulatory surface networks. Results suggest that in agricultural areas where ammonia concentrations and animal density are highest, air quality improvement lags behind the national average.

A Case of a Serum Sickness-Like Reaction After Postexposure Rabies Prophylaxis.

BACKGROUND: Serum sickness secondary to rabies postexposure prophylaxis is not well documented in the medical literature. Our case describes serum sickness after exposure to human-derived rabies immunoglobulin (HRIG) and three human diploid rabies vaccines (HDCV) in a young adult male. CASE REPORT: A 30-year-old previously healthy male patient presented to the Emergency Department with complaints of fever, rash, and jaundice, and had a hospital course complicated by biliary stenosis likely secondary to reactive periportal lymphadenopathy. His initial laboratory values demonstrated obstructive jaundice and slightly elevated complement component 4 levels. These symptoms likely are due to the course of HRIG and HDCV vaccines the patient completed after being exposed to a rabies-positive bat in his home. The patient was hospitalized for 8 days, during which he underwent an endoscopic retrograde cholangiopancreatography with sphincterotomy and biliary stenting. He had one repeat hospitalization for acute blood loss anemia attributed to sphincterotomy, which did not require transfusion or further intervention. Liver biopsy showed cholestatic hepatitis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Medical literature describing serum sickness or a serum sickness-like reaction occurring from exposure to HRIG or HDCV is sparse despite the commonality of postexposure rabies prophylaxis in health care. It is important to educate practitioners on this potential complication and highlight next potential consultations and treatments.

Modular Oxime Formation by a trans-AT Polyketide Synthase.

Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are enzymatic assembly lines that biosynthesize complex polyketide natural products. Relative to their better studied cis-AT counterparts, the trans-AT PKSs introduce remarkable chemical diversity into their polyketide products. A notable example is the lobatamide A PKS, which incorporates a methylated oxime. Here we demonstrate biochemically that this functionality is installed on-line by an unusual oxygenase-containing bimodule. Furthermore, analysis of the oxygenase crystal structure coupled with site-directed mutagenesis allows us to propose a model for catalysis, as well as identifying key protein-protein interactions that support this chemistry. Overall, our work adds oxime-forming machinery to the biomolecular toolbox available for trans-AT PKS engineering, opening the way to introducing such masked aldehyde functionalities into diverse polyketides.

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases.

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.

Proximal sesamoid bone microdamage is localized to articular subchondral regions in Thoroughbred racehorses, with similar fracture toughness between fracture and controls.

OBJECTIVE: To determine whether proximal sesamoid bone (PSB) microdamage and fracture toughness differ between Thoroughbred racehorses sustaining PSB fracture and controls. STUDY DESIGN: Cadaveric case-control. ANIMALS: Twenty-four Thoroughbred racehorses (n = 12 PSB fracture, n = 12 control). METHODS: Proximal sesamoid bones were dissected, and gross pathological changes and morphological measurements were documented. High-speed exercise history data were evaluated. Microdamage was assessed in fracture, fracture-contralateral limb (FXCL) and control PSBs using whole bone lead uranyl acetate (LUA) staining with micro-CT imaging or basic fuchsin histological analysis. Fracture toughness mechanical testing was carried out in 3-point-bending of microbeams created from PSB flexor cortices. Data were analyzed using ordinal logistic and linear regression models. RESULTS: Microdamage was detected most commonly in the articular subchondral region of PSBs via LUA micro-CT and basic fuchsin histology. There were no differences in microdamage between FXCL and control PSBs. Fracture toughness values were similar for FXCL (1.31 MPa√m) and control (1.35 MPa√m) PSBs. Exercise histories were similar except that horses sustaining fracture spent a greater percentage of their careers in rest weeks. CONCLUSION: Microdamage was detected in the articular region of PSBs but was not greater in horses sustaining catastrophic PSB fracture. Fracture toughness of PSB flexor cortices did not differ between FXCL and control PSBs. CLINICAL SIGNIFICANCE: Although uncommon, microdamage is localized to the articular region of Thoroughbred racehorse PSBs. Catastrophic PSB failure is not associated with lower PSB flexor cortex fracture toughness.

Comparative Effectiveness of Training with Simulators Versus Traditional Instruction in Veterinary Education: Meta-Analysis and Systematic Review.

One of the greatest challenges in veterinary education is adequately preparing students with the clinical skills they need to be successful health care providers. Integration of simulators, devices used to represent real world phenomena under test conditions, into the veterinary curriculum can help address challenges to clinical instruction. The use of simulators in veterinary education is increasing; however, their effectiveness remains unclear. This meta-analysis seeks to synthesize the evidence for simulator training in veterinary education to provide a consensus of effect, guide the integration of simulators into the curriculum, and direct the development of future simulation-based research in veterinary medicine. A systematic search identified 416 potential manuscripts from which 60 articles were included after application of inclusion criteria. Information was extracted from 71 independent experiments. The overall weighted mean effect size for simulator training was g = 0.49 for the random-effects model. The outcome measures of knowledge, time, process, and product all produced statistically significant mean effect sizes favoring simulation (d = 0.41, 0.35, 0.70, 0.53, respectively). A moderator analysis revealed that study characteristics and instructional design features moderated the effectiveness of simulator training. Overall, the results indicate that simulator training in veterinary education can be effective for knowledge and clinical skill outcomes.

Quality of referrals for glaucoma assessment: a cross-sectional survey of clinical data and outcomes.

PURPOSE: This study assessed the completeness of clinical information provided by ophthalmological and optometric referrals to glaucoma specialists consulting for open-angle glaucoma (OAG). METHODS: A retrospective, cross-sectional study of 72 internal referrals for evaluation of OAG in a multispecialty group practice was performed. The quality of the referral was assessed based on: (1) the completeness of the clinical triad of intraocular pressure measurement, visual field (VF), and cup-to-disk ratio for each eye; (2) the availability of the data necessary to calculate an ocular hypertension treatment study (OHTS) score; and (3) the presence of retinal nerve fiber layer (RNFL) imaging by mean of optical coherence tomography. RESULTS: The clinical triad was available in 57% of referrals, whereas an OHTS score was calculable in 24% of referrals (p < 0.001); RNLF imaging was available in 51% of referrals (p = 0.859). The completeness of clinical information was similar for ophthalmological and optometric referrals. From the date of referral to the time of the consultation, there was a significant increase in the availability of the clinical triad (57-65%; p = 0.013) and the OHTS score (24-5%; p = 0.004) but not for RNFL imaging (51-56%; p = 0.618). The most common missing clinical information was VF testing, which was absent in 42% of referrals. CONCLUSIONS: Key clinical data necessary for effective diagnosis and staging of OAG was lacking for many patients referred to glaucoma specialists.

Towards improved understanding of intersubunit interactions in modular polyketide biosynthesis: Docking in the enacyloxin IIa polyketide synthase.

Modular polyketide synthases (PKSs) are molecular-scale assembly lines comprising multiple gigantic polypeptide subunits. Faithful ordering of the subunits is mediated by extreme C- and N-terminal regions called docking domains (DDs). Decrypting how specificity is achieved by these elements is important both for understanding PKS function and modifying it to generate useful polyketide analogues for biological evaluation. Here we report the biophysical and structural characterisation of all six PKS/PKS interfaces in the unusual, chimaeric cis-AT/trans-AT PKS pathway responsible for biosynthesis of the antibiotic enacyloxin IIa in Burkholderia ambifaria. Taken together with previous work, our data reveal that specificity is achieved in the enacyloxin PKS by deploying at least three functionally orthogonal classes of DDs. We also demonstrate for the first time that cis-AT PKS subunits incorporate DDs with intrinsically disordered character, reinforcing the utility of such regions for achieving both medium affinity and high specificity at PKS intersubunit junctions. Overall, this work substantially increases the number of orthogonal DDs available for creating novel, highly-specific interfaces within cis- and trans-AT PKSs and their hybrids. It also reveals unexpected sequence/structure relationships in PKS DDs, identifying major current limitations to both accurately predicting and categorising these useful protein-protein interaction motifs.

Spinal cord involvement by atrophy and associations with disability are different between multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: The cervical and thoracic cross-sectional spinal cord area (CS-SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS-SCA is associated with disability. METHODS: The CS-SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing-remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti-aquaporin-4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS-SCA and disability were assessed by stepwise forward multiple linear regression. RESULTS: Thoracic CS-SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (P = 0.002 at T8/T9), whilst there was no difference in cervical CS-SCA between the two diseases. Cervical and thoracic CS-SCA had a negative correlation with EDSS scores in MS patients (P < 0.0001 at C3/C4 and P = 0.0002 at T8/T9) whereas only thoracic CS-SCA correlated with EDSS scores in NMOSD patients (P = 0.0006 at T8/T9). By multiple regression analyses, predictive factors for disability in MS were smaller cervical CS-SCA, progressive course, older age and a higher number of relapses, whilst those in NMOSD were smaller thoracic CS-SCA and older age. CONCLUSIONS: Thoracic CS-SCA is a useful predictive marker for disability in patients with NMOSD whilst cervical CS-SCA is associated with disability in patients with MS.

A systematic review of digital badges in health care education.

OBJECTIVES: A challenge to competency-based medical education is the verification of skill acquisition. Digital badges represent an innovative instruction strategy involving the credentialing of competencies to provide evidence for achievement. Despite increasing interest in digital badges, there has been no synthesis of the health care education literature regarding this credentialing strategy. The present authors proposed to address this gap by conducting the first systematic review of digital badges in health care education, to reveal pedagogical and research limitations, and to provide an evidence-based foundation for the design and implementation of digital badges. METHODS: A systematic search of the medical education literature from January 2008 to March 2019 was conducted using MEDLINE, Web of Science, CAB Abstracts and ScienceDirect. Included studies described digital badges in academic or professional medical education programmes in any health care profession. Included studies were appraised and quality assessment, methodological scoring, quantitative analysis and thematic extraction were conducted. RESULTS: A total of 1050 relevant records were screened for inclusion; 201 full text articles were then assessed for eligibility, which resulted in the identification of 30 independent papers for analysis. All records had been published since 2013; 77% were journal articles, and 83% involved academic health care education programmes. Scores for quality were relatively moderate. Thematic analyses revealed implications for the design and implementation of digital badges: learner characteristics may moderate student outcomes; the novelty effect can negate the value of digital badges, and educators may overcome instruction-related challenges with digital badges using design and implementation strategies such as the creation of badging ecosystems. CONCLUSIONS: The results indicate a growing momentum for the use of digital badges as an innovative instruction and credentialing strategy within higher education and provide evidence for outcomes within a learner-centred, competency-based model of medical education. There is a paucity of research to support the design and implementation of this credentialing system in health care education. The potential benefits necessitate future high-quality analyses reporting institutional, patient and workplace-based outcomes to evaluate the effectiveness and moderating conditions of digital badges.

Antibiotics modulate biofilm formation in fish pathogenic isolates of atypical Aeromonas salmonicida.

Atypical Aeromonas salmonicida causes furunculosis infections of non-salmonid fish, which requires antibiotic therapy. However, antibiotics may induce biofilm in some bacteria, which protects them against hostile conditions while allowing them to persist on surfaces, thus forming a reservoir for infection. The aim of this study was to determine whether atypical isolates of A. salmonicida increased biofilm in the presence of two antibiotics, florfenicol and oxytetracycline. A microtitre plate assay was used to quantify biofilm in the presence and absence of each antibiotic. Fifteen of 28 isolates formed biofilms under control conditions, while 23 of 28 isolates increased biofilm formation in the presence of at least one concentration of at least one antibiotic. For oxytetracycline, the most effective concentration causing biofilm to increase was one-quarter of that preventing visible bacterial growth, whereas for florfenicol it was one-half of this value. This is the first study to demonstrate that a bacterial pathogen of fish increases biofilm in response to antibiotics. Biofilm formation may increase the risk of re-infection in culture systems and this lifestyle favours the transmission of genetic material, which has implications for the dissemination of antibiotic-resistance genes and demonstrates the need for enhanced disease prevention measures against atypical A. salmonicida.

The effect of premature maternal separation on distress vocalizations and activity in kittens (Felis catus) during a brief nest separation.

It is unknown how premature maternal separation affects the responses of kittens to potentially stressful events. In the United States, thousands of kittens are orphaned each year due to death of the queen, neglect, or accidental separation by humans. Neonatal mammals emit distress calls and increase locomotion when socially isolated, suggesting that being separated from the nest is a stressful event. Increased vocalization and activity of isolated neonates may aid maternal retrieval or relocation of the nest. In the current study, we assessed the effects of early maternal separation on later vocalizations and activity of 49 kittens (28 orphaned, 21 mother-reared; 23 female, 26 male) from 11 litters (5 mothered, 6 orphaned) during an open field test when the kittens were one and three weeks of age. We conducted a total of 79 trials. Each kitten was placed individually in a 1-meter diameter pen away from the rest of the litter and/or mother for two minutes. The number of calls emitted and total activity (in seconds) were recorded for each kitten on every trial. We assessed the effects of age, sex, orphan status, and interactions between orphan status with sex and age on activity and vocalizations. Orphaned kittens were more active than mother-reared kittens at both times (t(46) = 4.62, p < 0.001), with an interaction between age and orphan status (t(28) = -2.84, p = 0.008). Orphaned kittens emitted more vocalizations at both times (Z = 2.38, p = 0.018), with an interaction between age and orphan status (Z = -3.18, p = 0.001). Orphaned kittens showed increased activity and vocalizations in response to a brief nest separation compared to mother-reared kittens. This effect was still present after over two weeks of maternal separation, suggesting that maternal separation may lead to long-term changes in stress responses. Future research should explore if such effects of maternal separation are present in older kittens or adult cats.

Is a Picture Worth a Thousand Words? Evaluating the Design of Instructional Animations in Veterinary Education.

Empirical evidence demonstrates that student learning outcomes improve when animations are developed in alignment with the design principles of the cognitive theory of multimedia learning (CTML). The extent to which these principles are used in the design of veterinary instructional animations is unknown. In this study, we reviewed the veterinary education literature for articles that discussed specific veterinary medical animations as learning resources. The 30 referenced animations accessed through this search were analyzed to determine whether they used the CTML's 11 major design principles. Analysis revealed that the animations most commonly adhered to only 4 principles: coherence, redundancy, modality, and spatial contiguity. The majority of the 11 CTML principles were used in fewer than 40% of the animations. We also examined the alignment between raters' perceptions of the effectiveness and enjoyment of the animations and adherence to the design principles. Analyses revealed that the animations deemed by raters as most enjoyable and effective did not utilize more design principles than animations they viewed as least enjoyable and effective. The results of this study indicate many missed opportunities to increase learning by developing animated learning resources according to empirically based design principles. Decisions to include specific animations in instruction should be based on whether the resources include elements that have been shown to increase learning rather than subjective perceptions of effectiveness and enjoyment.

Nurses and Fetal Alcohol Spectrum Disorders Prevention.

Women of reproductive age who are drinking alcohol and not using effective contraception are at-risk for an alcohol-exposed pregnancy, which could result in a child with a fetal alcohol spectrum disorder (FASD). Nurses are an important partner in addressing at-risk alcohol use. It is imperative for alcohol education to be incorporated into nursing curricula so that future nurses have the tools to identify at-risk alcohol use. Three universities have worked together to create Fetal Alcohol Spectrum Disorders: A Toolkit. This toolkit was designed for nurses to facilitate the recognition and prevention of FASD and address gaps that exists around alcohol use.

Correction: Uncovering the structures of modular polyketide synthases.

Correction for 'Uncovering the structures of modular polyketide synthases' by Kira J. Weissman, Nat. Prod. Rep., 2015, 32, 436-453.

The structural biology of biosynthetic megaenzymes.

The modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) are among the largest and most complicated enzymes in nature. In these biosynthetic systems, independently folding protein domains, which are organized into units called 'modules', operate in assembly-line fashion to construct polymeric chains and tailor their functionalities. Products of PKSs and NRPSs include a number of blockbuster medicines, and this has motivated researchers to understand how they operate so that they can be modified by genetic engineering. Beginning in the 1990s, structural biology has provided a number of key insights. The emerging picture is one of remarkable dynamics and conformational programming in which the chemical states of individual catalytic domains are communicated to the others, configuring the modules for the next stage in the biosynthesis. This unexpected level of complexity most likely accounts for the low success rate of empirical genetic engineering experiments and suggests ways forward for productive megaenzyme synthetic biology.